Summary Glucocorticoid-induced osteoporosis is the most common cause of secondary osteoporosis, and the primary cause before age 50. It affects over 0.5% of the general population, wherein 65% are women. In post- menopausal women and men aged 50 and over, treatment would be recommended in at least half based on the 2010 American College of Rheumatology guidelines. Adult stem cells are a promising class of regenerative cells, some lineages of which can be induced to differentiate into osteoblasts and potentially cure osteoporosis. We have shown that 250-fold nanofiber-expanded hematopoietic (CD34+) stem cells can reverse glucocorticoid-induced osteoporosis in an aged murine model. Now we have discovered a way to expand CD34+ stem cells over a million-fold while preserving their stemness, which promises to make this therapy cost effective. These cells can be obtained noninvasively from umbilical cord blood (UCB). UCB is readily available and is considered safe for human application for treating a variety of diseases such as leukemia and other blood disorders. If these million-fold expanded CD34+ stem cells can be shown to be safe and efficacious in reverting glucocorticoid-induced osteoporosis, this cell-based therapy may extend to other types of osteoporosis, and would represent a major paradigm shift. Patients with osteoporosis must undergo lifetime therapy with traditional therapeutics, whereas stem cells promise to be a 1 to 2 time treatment. Furthermore, patients will not have extended hospitalization nor surgery costs, as stem cell therapy in many cases is an outpatient IV infusion. Million-fold expansion provides the opportunity to reduce costs further, as one cord blood unit will be able to treat over 100 patients. The aims of this Phase I project are therefore to (a) determine the potential of million-fold expanded CD34+ stem cells to differentiate into osteoblasts, and (b) test the efficacy of million-fold expanded CD34+ stem cells for reverting glucocorticoid-induced osteoporosis in aged mice. If successful, this research will be extended to more severe forms of osteoporosis, and potentially provide a pathway towards a cost effective clinical regenerative treatment for this debilitating disease. It may also have extensions for the lower-cost treatment of leukemias and a variety of other blood disorders, which will be the subject of future investigations.